Ventricle pacing during atrial fibrillation episodes

ABSTRACT

An adaptive cardiac resynchronization therapy system delivers biventricular stimulation to the heart with dynamic AV delay and VV interval. The stimulation is modified continuously in correlation with the hemodynamic performance of the heart. The system uses a spiking neural network comprising spike controller ( 42 ) that learns to associate the VA interval based on hemodynamic sensor temporal patterns. The associated VA interval replaces the sensed atrial event signal during atrial fibrillation episodes.

FIELD OF THE INVENTION

The present invention relates generally to cardiac pacing and defibrillating and more specifically to cardiac pacing during arrhythmias.

BACKGROUND OF THE INVENTION

Atrial fibrillation (AF) is the most common cardiac rhythm disorder and it affects an estimated 2.3 million adults in the United States, the majority of who are over the age of 65 years. Far from benign, AF can lead to stroke, tachycardia-induced cardiomyopathy, and congestive heart failure. AF accounts for about 15% of all is strokes that occur each year in the United States. The number of patients with AF is increasing throughout the industrialized world as the population ages. In the United States, the prevalence of AF is expected to grow 2.5-fold to 5.6 million by 2050, and over half of those afflicted will be aged 80 or older As the burden of this disorder grows, increased emphasis will be placed on developing more effective ways to treat AF to reduce its associated morbidity and mortality (James L. Cox, MD, Surgical Management of Atrial Fibrillation, Medscape Cardiology, May 2005). Implanted pacemakers and intracardiac cardioverter defibrillators (ICD) deliver therapy to patients suffering from various heart-diseases (Clinical Cardiac Pacing and Defibrillation, 2^(nd) edition, Ellenbogen, Kay, Wilkoff, 2000). Dual chamber pacemakers pace the right ventricle with synchrony to the sensed atrial event, with a given delay, the atrioventricular (AV) delay. Cardiac Resynchronization Therapy (CRT) devices, i.e. biventricular pacemakers, pace both ventricles, and also synchronize according to the sensed atrial event signal.

However, a significant proportion of patients having a dual chamber pacemaker or biventricular pacemaker suffer also from atrial fibrillation episodes, possibly long lasting. These patients will not benefit from their dual chamber pacemaker or biventricular pacemaker during an episode since both devices synchronize according to the sensed atrial events that are not reliable during atrial fibrillation episodes, and hence will not deliver physiologic pacing during atrial fibrillation episodes.

In PCT publication WO0038782 a pacing system is disclosed, featuring a mode switching feature and ventricular rate regularization (VRR) function capable of stabilizing or regularizing ventricular heart rate during chronic or paroxysmal atrial tachyarrhythmia. The VRR function accomplishes this result by adjusting pacing rate according to the pattern of the most recent series of sensed or paced ventricular events.

In US2005187585 patent application, a method is disclosed for adaptively smoothing ventricular rate during atrial fibrillation (AF). According to this method, the pacing delivered by a pacing device is switched to a non-atrial synchronized mode when AF is detected. The ventricular escape interval (VEI) is modulated beat-by-beat around a physiological interval zone (PIZ), which is determined by the pre-arrhythmia ventricular rate or the output of rate responsive sensor.

Selective atrioventricular nodal (AVN) vagal stimulation (AVN-VS) has emerged as a novel strategy for ventricular rate (VR) control in atrial fibrillation (AF). AVN-VS is delivered to the epicardial fat pad that projects the parasympathetic nerve fibers to the AVN. Although AVN-VS preserves the physiological ventricular activation sequence, the resulting rate is slow and irregular. This issue is discussed in “Ventricular Rate Control by Selective Vagal Stimulation Is Superior to Rhythm Regularization by Atrioventricular Nodal Ablation and Pacing During Atrial Fibrillation”, by Shaowei Zhuang, et al, Circulation. 2002; 106:1853. The authors indicate that the AVN-VS although producing a superior hemodynamic performance as compared to an ablation and pacing approach, results in irregular ventricular contractions rate, i.e. irregular sensed R-R intervals.

P. Taggart and P. Sutton argue In “Termination of Arrhythmia by Hemodynamic Unloading”, published in Cardiac Mechano-Electric Feedback & Arrhythmia, by Kohl, Sachs and Franz, Elsevier Saunders, 2005, that hemodynamic unloading should be anti arrhythmic: “ventricular or atrial unloading should tend to be protective against focal tachycardia caused by triggered activity. The foregoing theoretical predictions are supported by several studies in different animal models in which arrhythmia were induced by increased stretch or volume loading.”

The various methods presented above for rate regulation during atrial fibrillation episodes are based on heart rate regulation and do not take into account the exact cardiac cycle timings when pacing the ventricles during atrial fibrillation while the AVN-VS method preserves the physiological ventricular activation sequence but produces irregular ventricular contractions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic description of an adaptive CRT employing association of a ventricle-atrial (VA) interval with temporal patterns of hemodynamic sensor;

FIG. 2 is a schematic description of the neural network architecture performing biventricular pacing and VA interval association based on intracardiac electrograms (IEGMs) and hemodynamic (Impedance) sensor.

FIG. 3 is a flow diagram description of the switching between associated ventricle-atrial (VA) interval and sensed atrial event timing based pacing according to atrial fibrillation detection.

FIG. 4 is a state diagram describing switching between associated and sensed atrial timing based pacing.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the present invention implanted hemodynamic sensors are used in a way that reflects the hemodynamic performance of the ventricle, which is likely to be reliable also during atrial fibrillation episodes in order to unload hemodynamic stress and suppress the arrhythmia. The hemodynamic sensor can be used to synchronize pacing with the cardiac cycle timings and ventricular pacing in dual chamber devices or bi-ventricular pacing in CRT devices can be delivered with optimal timings also during atrial fibrillation episodes.

In accordance with the present invention, the timing of the subsequent atrial event is predicted relative to the preceding ventricle event by association of temporal patterns of hemodynamic sensor with a VA interval. By exploiting both this prediction and hemodynamic sensors that reflect ventricle function, a dynamic optimization of the pacing intervals can be performed for the particular patient. Such a combined tool is useful during atrial fibrillation incidents, and hence provides a more physiologic pacing for patients suffering from atrial fibrillation episodes.

The system of the present invention employs an implanted adaptive biventricular pacemaker (referred to also as a CRT devices), or adaptive dual chamber pacemakers or ICD devices as disclosed in PCT application WO 2005007075 by the inventor of the present application, the contents of which are incorporated herein by reference. With an adaptive CRT device both AV delay and the VV interval vary dynamically in response to hemodynamic inputs from sensors in a closed loop system such that the stroke volume at a given heart rate is maximized online and continuously. This system therefore implies a feedback control. As described in FIG. 1, the system of the present invention consists of an adaptive CRT device system equipped with a neural network processor for temporal pattern detection trained to associate the next atrial event timing relative to the preceding ventricle event. Spiking neural network processor 12 is the learning module, working as a slave processor with micro-controller 14. Block 16, which represents a pulse generator and operational amplifier(s), is the analogue interface to patient heart electrodes 18. The atrial and biventricular electrodes are implanted, namely, the right atria lead, right ventricular lead and left ventricular lead. Physiologic sensors 22 implanted at the right and left ventricles, are any sensors known in the art, for example chamber impedance sensors, chamber pressure sensors and accelerometers. Box 24 designates all the modules implanted in the patient.

In FIG. 2 to which reference is now made, the architectural aspects of a neural network that performs both biventricular pacing and atrial event association with is temporal patterns of hemodynamic sensors are shown. Preferably, the neural network processor of the invention is a spiking neural network processor having three layers. An input layer with temporal decoder synchronizer 34, middle layer 36, and output layer 38. Spike controller 42 manages the neural network operations. The architecture of the temporal pattern detection neural network module for the atrial event timing relative to the preceding ventricle event, i.e. the VA interval, is similar to the one described above, having temporal decoder synchronizer 60, middle layer 62, and output layer 64. A detailed description of the temporal pattern detection neural network is given below. The three important outputs of the learning module, the neural network processor, are AV delay, VV interval and the associated VA interval.

The adaptive CRT neural network processor architecture and its operation is described in WO 2005/007075 the contents of which are incorporated herein by reference. The present invention provides a system and a method that in addition to bi-ventricular pacing or right ventricular pacing replace the sensed atrial event signal during atrial arrhythmia episodes with an associated VA interval internally in the timing circuits that control the ventricular and bi-ventricular pacing and are therefore capable of continuing to pace with optimal timing the ventricles during atrial fibrillation as well.

The temporal pattern detection neural network is trained using a supervised learning rule continuously supplied by the micro-controller using the hemodynamic sensor signal as an input from the right or left ventricle chambers. The neural network learns how to map the temporal patterns of the hemodynamic sensor into VA intervals as long as normal sinus rhythm is detected. Whenever atrial fibrillation occurs and is detected, the neural network associates VA interval correlated with the temporal patterns of the hemodynamic sensor that takes over the atrial sensed event as will be explained below.

Temporal Pattern Recognition with Spiking Neurons

The first stage in the temporal pattern detection neural network, is a pre-processing stage for the hemodynamic sensor temporal input signal with a temporal synchronizer. The synchronizer excites selectively an array of dynamic synapses of the middle layer. The middle layer has typically 200 dynamic synapses that are arranged in a matrix having 10 columns and 20 synapses in each column. The temporal synchronizer is triggered every cardiac cycle by the ventricle-sensed electrical event, i.e. ventricular IEGM, and following the trigger it excites selectively in a time sequence a group of dynamic synapses at each column according to the temporal values of the input hemodynamic sensor signal at the excitation times. At the output layer there are typically 10 leaky integrate-and-fires (I&F) neurons, one for each column of dynamic synapses, that accumulate the post synaptic responses excitations (PSR) of the synapses in the middle layer. All the I&F neurons are trained to fire at the same target time which is the sensed VA interval. The output layer I&F neurons are trained to fire at the target time and a fuzzy average result using a membership function for each I&F neuron is calculated as the final result of the neural network i.e. the associated VA interval. The fuzzy average calculation, to be further elaborated below, increases the prediction accuracy of the temporal pattern detection neural network (TPDNN). The combination of fuzzy logic and neural network for control systems takes advantage of both techniques, as discussed in “Understanding Neural Networks and Fuzzy Logic: basic concepts and applications” by Stamatios V. Kartalopoulos, Wiley-IEEE Press, August 1995 incorporated herein by reference.

Temporal Pattern Recognition Learning Scheme

In 1949 Donald Hebb proposed that ‘associative learning’ involved a simple cellular mechanism. His hypothesis known as ‘Hebb's learning rule’ claimed that “coincident activity in both cells involved is critical for strengthening the connections (associations) between the pre-synaptic and post-synaptic neurons”. Hebb's learning rule states that “when an axon cell A excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A′s efficacy, as one of two cells firing B, is increased.” The present invention implements Hebbian learning rules as described below

The dynamic synapses of the pattern recognition network adapt their internal time delay parameter, τ_(ij), which is the time delay parameter between a pre-synaptic excitation by the temporal synchronizer to the synapse post synaptic response (PSR). The synaptic time delay parameter changes according to a supervised learning rule where the supervised target time is the sensed atrial event measured from the previous ventricle contraction. The Hebbian learning rule used with the spiking neurons network performing temporal pattern recognition of the present invention is formulated as follows:

Equation 1:

τ_(ij)=τ_(ij) +η*R _(ij)  (1)

where: i=0 . . . , 9 is the I&F neuron index and the column index. j=0, . . . , 19 is the synapse index within a column. η is the learning rate coefficient. R_(ij) is a function of the relative timing of the firing of the I&F neuron, T_(i) and the target time, P_(i), as shown in Equation 2 below.

$\begin{matrix} {R_{ij} = \left\{ \begin{matrix} {+ 1} & {{{{if}\mspace{14mu} T_{i}} < P_{i}},} \\ {- 1} & {{{{if}\mspace{14mu} T_{i}} > P_{i}},} \end{matrix} \right.} & (2) \end{matrix}$

In each cardiac cycle the synapses that are excited by the temporal synchronizer starts incrementing an internal counter. When the firing time of the I&F neuron, T_(i), occurs before the internal time delay parameter, τ_(ij), expires the synapse state is stored as a Pre Hebb state. When the firing time occurs within a predefined short time interval, Δ, just after the expiration of τ_(ij) the synapse state is stored as a Hebb state. When the firing time of the I&F neuron occurs later, the synapse state is stored as a Post Hebb state. The post synaptic response (PSR) is emitted by the synapse in the Hebb state and is accumulated on the membrane potential of the post synaptic integrate and fire neuron. Note that according to Equation 2 the relative timings of the firing time T_(i), the target time P_(i), determines if the internal time delay parameter is incremented or decremented

Associated VA interval and Hit Count Rate Membership Function

A hit count rate membership function, f (Ti), is defined as the number of hits, or the hit count rate, of the I&F neuron that fires in the vicinity of the target time in a time frame of 32 cardiac cycles. The maximal value for the function is therefore 32 when the I&F neuron fires at the correct target time every cardiac cycle, and the hit count rate membership function is zero when the I&F neuron fires constantly out of the time window. For each I&F neuron the hit count rate membership function is calculated and a normalized average is calculated according to Equation 3 below

Associated VA=Σf(Ti)*Ti/Σf(Ti)  (3)

Where Ti is the firing time of I&F neuron i and the summation is done over all the spiking neurons of the output layer.

Equation 3 defines the associated VA interval of the TPDNN using the hit count rate membership function. The associated VA is used later to replace the sensed VA interval during atrial fibrillation episodes.

In FIG. 3 to which reference is now made, a flow diagram describes the switching decision the system makes between a sensed timing based pacing procedure and the associated timing based pacing procedure. In step 82 the atrial fibrillation detection unit verifies the presence of atrial fibrillation. If fibrillation is detected, the supervised training task is turned off, the neural network synaptic weights are frozen, and the associated VA interval is obtained in step 84 from the TPDNN as given in Eq. 3 above, is obtained beat after beat with the hemodynamic sensor input used as reference. The associated VA interval replaces the sensed atrial event for synchronizing the bi-ventricular pacing feedback task performed by the adaptive CRT device described in FIG. 2 to which reference is again made. If fibrillation is not detected, pacing continues according to the sensed atrial event during normal sinus rhythm in step 86. In this manner the CRT task continues undisturbed during an atrial fibrillation episode. The bi-ventricular pacing feedback task as explained in details in International Patent publication WO 2005/007075, for example, can continue to resynchronise the AV delay and VV timings online during a fibrillation episode. In such case, the system uses the hemodynamic sensors temporal patterns as reference, being relative to the associated VA event that replaces the normal sensed atrial event. When a normal atrial sinus rhythm is recovered, the device controller is switched back to using the natural detected atrial signal and also the VA association supervised learning task continues to learn to associate the hemodynamic sensor input temporal patterns into a VA intervals as explained above. It should be stressed that the two back and forth is switching mechanisms described above, i.e. the adaptive CRT vs. non adaptive CRT operational modes and the sensed atrial event vs. associated VA interval operational modes are independent of each other.

In the case of atrial fibrillation which is conducted to the ventricle, the hemodynamic performance of the ventricle will also be disturbed significantly and the association of the VA interval can fail. In such case the ventricular pacing relating to the associated VA interval is stopped and anti-tachycardia pacing (ATP) or a defibrillation shock might be the only effective therapy that can recover normal heart rhythm and function.

In FIG. 4 to which reference is now made, a state diagram relating to another preferred embodiment of the present invention is described. In accordance with this embodiment the control system switches back and forth between two states. One state uses associated VA interval instead of the sensed atrial event, also with a normal sinus rate. The other state uses the sensed atrial event. The system initializes with sense operation mode, 90, after the convergence of the VA association task 92 it switches to operate according to the associated VA interval, and the sensed VA interval is used thereafter only for on-line supervised learning while the associated VA interval value is used for the timing cycles of the micro-controller replacing the sensed atrial event in operation mode 94. When a failure takes place, such as a large deviation of the associated VA interval from the sensed atrial event or any other pre-defined failure, the system switches back, in transition 96, to use the sensed atrial event.

There are two reasons to prefer working with the associated operation mode. First, the learned VA intervals association according to hemodynamic sensor temporal patterns reflects closely the hemodynamic cycle, i.e. the diastolic and systolic cycles and even more specifically the passive and active filling times, the iso-volumetric contraction and the ejection phase. Therefore, the associated operation mode can be a more accurate indication for cardiac cycle timing associated with implanted pacemaker systems then the local sensed atrial IEGM signal. It is assumed therefore that by using the associated VA interval according to hemodynamic sensor temporal patterns, better pacing can be achieved with better AV synchrony to produce better clinical results as compared to synchronizing based on the sensed IEGM atrial lead. Second, when the prediction error is smaller than the accumulated errors due to all noise sources in the system, such as possible lead movements and signal degradation, sampling and digitization errors, and any other noise in the implanted electronic circuits, the learned associated atrial event is closer to the underlying physiological system timings and can correct the accumulated error.

Synaptic Stability—Plasticity Dilemma

What are the steady state optimal values of the synaptic weights that provide the best performance? It depends on the neural network architecture and also on environmental variables that might change with time. Hence the optimal synaptic weights are functional of time and environment states and when the environment is dynamic, such as the heart muscle, the neural network architecture must be flexible enough to adapt its synaptic weights accordingly to ensure best performance. Therefore, in accordance with the present invention the steady state value of the synaptic weight are changeable with time with the present application. In his above cited book, Stamatios V. Kartalopoulos, in page 59, discusses the notion of elasticity of the learning system. It is discussed how a learning system can be designed to remain plastic or adaptable enough to learn new things whenever they appear and yet remain stable enough to retain previously learned knowledge.

With the neural network temporal pattern recognition architecture presented here each synapse change its learning rate parameter, η, according to its local activation state and a value of the membership function calculated for each I&F neuron, i.e. the hit count rate. When the dynamic synapse is highly activated in Hebb state and the hit count rate is high, the learning rate, η, is decreased and hence synapse gains selective stability. The mechanism for adjusting selectively the learning rate parameter brings stability and reduces the occurrence of losing previously learned patterns by new input patterns. A neural network system employing a smaller learning rate parameter becomes a slow learner but still maintains a reduced plasticity. New patterns that excite other synapses in the middle layer will be processed with higher plasticity according to the selective stabilization mechanism described here. The selective stabilization process is improved further by adding a global small leakage component to all synapse excitation that cause a loss of activation with a constant slow rate. This mechanism affects synapses that were previously highly activated but later became inactive for a long period of time, to lose slowly their activation level and thus to increase their plasticity through acquiring a larger learning rate coefficient.

In accordance with the present invention, the spiking neural network architecture strategy is to change for each synapse the learning rate coefficient locally and selectively. Synapses that were active and cause hits at the target time and hence a saturation of the hit count rate membership function gain stability. The neural network architecture described above demonstrates both plasticity and stability, and is more stable with regards to noise and erroneous temporal patterns, yet it is still a fast learner of new temporal patterns due to the selectivity of the learned learning rate coefficients.

ADVANTAGES OF IMPLEMENTING THE INVENTION

Applying the method of the present invention, the ventricular pacing is synchronized with the cardiac cycle timings even during atrial fibrillation and hence can unload hemodynamic stress and may further suppress the arrhythmia, according to argumentation of Taggart and Sutton quoted above. It is expected to be clinically beneficial for both congestive heart failure (CHF) patients treated with CRT devices and for patients treated with dual chamber pacemakers and ICD's. 

1. A system that learns to associate ventricle-atrial (VA) intervals with temporal patterns of at least one hemodynamic sensor using neural network processing, comprising: an input layer temporal synchronizer performing a pre-processing stage of at least one hemodynamic sensor input; a middle layer consisting of dynamic synapses, wherein an array of dynamic synapses are grouped in columns and an output layer consisting of one integrate and fire neuron for each dynamic synapse column of the middle layer and wherein a hit count rate membership function is for each integrate and fire neuron is calculated and an average normalized summation of all integrate and fire neurons gives the association of a VA intervals with the input hemodynamic sensor temporal patterns in all heart conditions.
 2. A system according to claim 1 wherein said spiking neural network synapses are trained applying a Hebbian learning rule and wherein a learning rate parameter is changed locally and selectively in each synapse module according to the value of the hit count rate membership function of the post synaptic integrate and fire neuron and according to the activation state of the synapse such that a synapse that was active and caused a saturation of the hit count rate membership function of the output layer integrate and fire neuron reduce its learning rate parameter.
 3. A system according to claims 1 and 2 wherein in each synapse a local and selective learning rate parameter is adjustable separately in order to improve stability and preserve plasticity of the artificial neural network.
 4. An adaptive cardiac resynchronization therapy system, delivering biventricular stimulation to the heart with dynamic AV delay and VV interval, wherein said stimulation is modified continuously in correlation with the hemodynamic performance of the heart, and wherein said system uses a spiking neural network as in claim 1 that learns to associate the VA interval based on a hemodynamic sensor temporal patterns wherein the associated VA intervals replace the sensed atrial event signal during atrial fibrillation episodes.
 5. An adaptive dual chamber pacemaker or ICD system, delivering ventricular stimulation to the heart with dynamic AV delay, wherein said stimulation is modified continuously in correlation with the hemodynamic performance of the heart, and wherein said system uses a spiking neural network as in claim 1 that learns to associate the VA interval based on a hemodynamic sensor temporal patterns wherein the associated VA interval replace the sensed atrial event signal during atrial fibrillation episodes.
 6. A system according to claim 1 wherein said spiking neuron network architecture is implemented in a processor operating with low clock frequency at the range 1-10 KHz and with synaptic weight adaptation deriving reference from a hemodynamic sensor input and implementing a Hebbian learning rule.
 7. A system for providing adaptive cardiac resynchronization therapy or dual chamber pacing or intracardiac cardioverter defibrillation wherein said system switches back an forth between a sensed atrial operation mode and an associated VA interval operation mode based upon temporal pattern recognition of the spiking neural network as in claim 1 wherein the associated VA interval replace the sensed atrial event signal as long as the spiking neural network associated VA interval is valid and where a switch back to working with the sensed event occurs when the VA interval association is poor or any system failure occurs.
 8. A system as in claims 1 to 7 wherein said VA interval is obtained online using any other neural network architecture or learning module.
 9. A method for regulating a controlled delivery of a physiologically active agent to a patient comprising the steps of: obtaining continuous signal from at least one sensor monitoring at least one physiological parameter of said patient; processing said at least one continuous signal using an algorithmic processing module and a learning module, and wherein said learning modules carries out adaptive learning in connection with said at least one sensor wherein said learning is controlled and supervised by said algorithmic module, and delivering a physiological signal by a delivery module in response to said processed signal, wherein said delivery module is controlled by said algorithmic module.
 10. A method as in claim 9 for delivering biventricular pacing to congestive heart failure patients that provides biventricular pacing also during atrial fibrillation episodes comprising the steps of: programming initial atrioventricular (AV) delay parameter VV (interventricular delay) interval parameter of said algorithmic module; learning to associate the VA interval with temporal patterns of hemodynamic sensor during normal sinus atrial rate and switching on according to the associated VA interval when atrial fibrillation is detected; switching back on in correlation with the sensed atrial event when normal sinus rhythm is recovered; providing pacing in a non-adaptive CRT mode whereby pacing is provided according to said pre-programmed AV delay and VV interval parameters, switching to an adaptive CRT mode wherein said AV delay and VV interval change dynamically in order to achieve optimal hemodynamic performance, and wherein said adaptive mode is limited to perform above a low limit of hemodynamic performance, and switching back to the non adaptive CRT mode whenever the hemodynamic performance drops below a low limit of hemodynamic performance or a sensor failure or any other system failure is detected.
 11. A method for regulating a controlled delivery of a physiologically active agent to a patient as in claim 9 as used for delivering ventricular pacing in dual chamber pacemakers or intracardiac cardioverter defibrillators (ICDs) that manages ventricular pacing also during atrial fibrillation episodes comprising the steps of: programming initial AV (atrioventricular) delay parameter of said algorithmic module; learning to associate the VA interval with temporal patterns of hemodynamic sensor during normal sinus atrial rate; switching to working in correlation with the associated VA interval when atrial fibrillation is detected; switching back to working in correlation with the sensed atrial event when normal sinus rhythm is recovered; providing pacing in a non-adaptive mode whereby pacing is provided in correlation with said pre-programmed AV delay; switching to an adaptive mode wherein said AV delay changes dynamically in order to achieve optimal hemodynamic performance, and wherein said adaptive mode performs only above a low limit of hemodynamic performance, and switching back to the non adaptive mode whenever the hemodynamic performance drops below a low limit of hemodynamic performance or a sensor failure occurs or any other system failure is detected.
 12. A method for regulating a controlled delivery of a physiologically active agent to a patient as in claim 9 whereby biventricular pacing is delivered that uses an associated VA interval replacing the sensed atrial event in the controller timing cycles, comprising the steps of: programming initial AV delay parameter interventricular (VV) delay interval parameter of said algorithmic module; learning to associate the VA interval with temporal patterns of hemodynamic sensor in correlation with the sensed atrial event; switching to working in correlation with the associated VA interval when a convergence of learning occurs; switching back to working in correlation with the sensed atrial event when failure occurs; providing pacing in a non-adaptive CRT mode whereby pacing is provided in correlation with said pre-programmed AV delay and VV interval parameters; switching to an adaptive CRT mode wherein said AV delay and VV interval change dynamically in order to achieve optimal hemodynamic performance, and wherein said adaptive mode is limited to perform above a low limit of hemodynamic performance, and switching back to the non adaptive CRT mode whenever the hemodynamic performance drops below a low limit of hemodynamic performance or a sensor failure or any other system failure is detected.
 13. A method regulating a controlled delivery of a physiologically active agent to a patient as in claim 9 for delivering ventricular pacing in dual chamber pacemakers or intracardiac cardioverter defibrillators, wherein an associated VA interval can replace the sensed atrial event in the controller timing cycles, comprising the steps of: programming initial AV (atrioventricular) delay parameter of said algorithmic module; learning to associate the VA interval with temporal patterns of hemodynamic sensor in correlation to the sensed atrial event; switching to working according to the associated VA interval when convergence of learning occurs; switching back to working according to the sensed atrial to event when failure occurs; providing pacing in a non-adaptive mode whereby pacing is provided according to said pre-programmed AV delay; switching to an adaptive mode wherein said AV delay changes dynamically in order to achieve optimal hemodynamic performance, and wherein said adaptive mode is limited to perform above a low limit of hemodynamic performance, and switching back to the non adaptive mode whenever the hemodynamic performance drops below a low limit of hemodynamic performance or a sensor failure or any other system failure is detected. 